It has long been recognized that thrombin not only functions as a final protease of coagulation cascade, which catalyzes the decomposition of fibrinogen to produce fibrin, but is also a multifunctional molecule that acts on various cells including platelet. While involvement of a “thrombin receptor” in such cell response has been presumed, and biochemical investigations relating to receptor characteristics in the platelet have been continued, the substance of the molecule has remained unknown. In 1990, a report documented thrombin receptor expression and receptor signaling by injecting human umbilical vein endothelial mRNA into Rana catesbeiana oocyte, showing the similarity to vascular endothelial expression thrombin receptor that had been reported. In 1991, the following year, two groups simultaneously reported cDNA cloning of PAR-1 in human and hamster (Cell, 1991, Vol. 64, pp. 1057-1068; FEBS, 1991, Vol. 288, pp. 123-128). A homology search of cDNA clarified that these receptors belong to G protein-coupled receptor superfamily and the report by the former showed that a limited decomposition of R41-S42 peptide bond in the PAR-1 N-terminal extracellular domain was necessary for receptor activation. In addition, it was demonstrated that 5-6 amino acid residue peptide corresponding to a new receptor N-terminal sequence could be a PAR-1 activating agonist (thrombin receptor agonist: TRAP). From a research using the TRAP, a wide variety of physiological actions of PAR-1 such as platelet activation, vascular, bronchial and gastrointestinal smooth muscle contraction and the like have been confirmed (Journal of the Pharmaceutical Society of Japan, 2001, Vol. 121, pp. 1-7). As mentioned earlier, expression of PAR-1 has been confirmed in almost all organs of living organisms including platelet, vascular smooth muscle, gastrointestinal tract smooth muscle, vascular endothelium, monocyte, T cells, fibroblast, renal glomerular mesangial cell and the like, strongly suggesting its involvement in various pathologies. Therefore, a PAR-1 antagonist is considered to be useful as a drug for the prophylaxis or treatment of various diseases.
Heretofore, compounds having a PAR-1 antagonistic action have been disclosed, for example, in WO01/00576, WO01/00657, WO01/00659, WO02/68425, WO02/85850, WO02/88092, WO02/88094, U.S. Pat. No. 6,544,982, Bioorg. Med. Chem. Lett., 2001, Vol. 11, pp. 2691-2696, Bioorg. Med. Chem. Lett., 2001, Vol. 11, pp. 2851-2853 and the like.
Moreover, a triazole derivative having a particular structure is described to have, for example, an FXa inhibitory action in WO99/32454, a glycine transporter inhibitory action in DE10315570A1, and a cytokine inhibitory activity in WO2004/050642. However, the derivative is not described or suggested to have a thrombin receptor antagonistic action, and is different from the triazole derivative of the present invention in the structural characteristics.